The overall goals of this project are to establish and pursue an innovative approach combining discovery studies in mammalian systems with translational and functional studies in the powerful genetic model organism Drosophila melanogaster as a novel strategy to identify and characterize genes and proteins underlying the behavioral changes that occur during the development of psychosis. In the search for new medical therapies, and in particular treatments for disorders of the central nervous system involving serotonin, like schizophrenia, psychosis, and depression, there has been increasing recognition that identification of a single biological target is unlikely to be a recipe for success;a broader perspective is required. Systems biology is one such approach, and has been increasingly recognized as a crucial and dynamic area of research, as it places specific molecular targets within a context of overall biochemical action. Understanding the complex interactions between the components within a given biological system that lead to modifications in output, such as changes in behavior, may be important avenues of discovery to identify new therapies. Within this framework, our underlying hypothesis is that molecular events, such as gene expression changes, influenced by aberrant serotonin receptor activation in specific regions of the brain, represent molecules that directly participate in, or regulate signal transduction networks that underlie normal cognitive processes that when perturbed lead to neuropsychiatric disorders. Here, we propose a series of experiments following a systems based approach to determine the functional and behavioral role of specific genes and proteins that respond to pharmacological activation of specific neurotransmitter receptors in the prefrontal cortex of rat brain in a proposed animal model of the neurochemical and genetic events underlying psychosis and schizophrenia. We will: 1) Identify additional, and perhaps more relevant, genes and proteins in specific regions of the rat prefrontal cortex through functional genomic, proteomic, and gene expression analysis;2) Examine the functional role of these genes and proteins in behaviors in translational studies in the fruit fly, Drosophila melanogaster. We strongly believe that this multidisciplinary systems-based approach combining mammalian CNS pharmacology and whole animal studies in our powerful genetic Drosophila model, is the best route to follow to achieve our goals. Significantly, our results may lead to novel avenues for therapeutics to treat such devastating diseases as schizophrenia and psychosis. PUBLIC HEALTH RELEVANCE: Project Narrative: Schizophrenia is a debilitating neuropsychiatric disorder that affects about one out of every 100 Americans at a cost to the U.S. economy of nearly $63 billion/year. New approaches towards understanding underlying schizophrenia mechanisms are urgently needed in order to further understand and treat this disorder, as well as other psychiatric disorders. Here, we are proposing a systems based approach to identify molecular and genetic factors underlying psychosis related disorders that involve serotonin by performing target discovery and functional studies in mammalian-based systems, and translating function to behavior in the powerful genetic model Drosophila melanogaster.